NE-AUA 2006 Annual Meeting, September 28 - 30, 2006, The Westin Hotel & Rhode Island Convention Center Providence, Rhode Island
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Erlotinib and Bladder Cancer: Impact on Activation and Downstream Signaling of the Epidermal Growth Factor Receptor
Micah A. Jacobs, M.D., Chad Wotkowicz, M.D., Egbert D. Baumgart, M.D., Brasil Silva Neto, M.D., Kimberly M. Rieger-Christ, PhD, John A. Libertino, M.D., Ian C. Summerhayes, PhD.
Lahey Clinic, Burlington, MA,

Background: Activation of the epidermal growth factor receptor (EGFR) can occur via mutation. In patients with non small cell lung cancer, mutations in the kinase domain of this gene are associated with clinical responsiveness to the EGFR inhibitor, erlotinib. We have found that only 5% (6/112) of bladder tumors harbor EGFR mutations although forty to sixty percent overexpress EGFR. The goal of this study was to establish the frequency of EGFR activation in bladder cancer and to determine whether the activation status of EGFR determines sensitivity to erlotinib.
Methods: Specimens from 213 bladder tumors resected at the Lahey Clinic were organized into tissue microarrays, stained for phosphorylated EGFR (pEGFR) and analysed using the Chi square test. Growth inhibition and cell killing effects of erlotinib were evaluated in a panel of bladder carcinoma cell lines (J82, MGHU1, 5637, BC16.1, EJ) in MTT and clonogenic assays. Cell lines were treated with epidermal growth factor (EGF-20μg/ml) in the presence and absence of erlotinib. Analysis of different signaling events were determined in Western blot analysis.
Results: Activation of EGFR, as defined by phosphorylation of the receptor, was identified in vivo in 93/213 (44%) tumor samples. Membrane localized pEGFR had no significant prognostic indication for tumor behavior or patient survival. Erlotinib inhibited the growth of bladder carcinoma cells with an IC50 range of <1μM to 50 μM. Three cell lines (5637, BC16.1, EJ) displayed high and two (J82, MGHU1) displayed low sensitivity to the drug. Within the panel of bladder carcinoma cell lines all displayed elevated phosphorylation of EGFR in the presence of EGF demonstrating a functional ligand/receptor complex. However, the sensitivity of cells to erlotinib remained unchanged in the presence of EGF. Treatment with erlotinib inhibited activation of EGFR, MAPK, AKT and STAT3 in all cell lines with a significant reduction of c-myc expression observed only in cells sensitive to erlotinib.
Conclusions: Although phosphorylation of EGFR is commonly found in bladder cancer this activation status does not define sensitivity to the action of erlotinib. However, differential sensitivity to erlotinib was recorded within a panel of bladder carcinoma cell lines where deactivation events were identified in downstream signaling. Presently, the mechanism defining sensitivity to erlotinib in bladder carcinoma cells is ill-defined although altered c-myc expression is linked to differential response. Even in the absence of EGFR mutations erlotinib has promise as a new therapeutic agent in bladder cancer.


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